The mechanisms of idiosyncratic drug reactions (IDRs) are unknown; however, most appear to be immune-mediated. Their idiosyncratic nature and the paucity of animal models make mechanistic studies very difficult. One of the few animal models is penicillamine-induced autoimmunity in Brown Norway rats. The major focus of this thesis was the use of this model to study the interaction between penicillamine and macrophages, the involvement of Th17 cells, and extension of this model to idiosyncratic drug-induced liver injury. One of the costimulatory signals leading to T cell activation appears to be reversible Schiff-base formation between an amine on T cells and an aldehyde on macrophages. We hypothesized that penicillamine binds to these aldehydes leading to macrophage activation and autoimmunity. By using biotinylated aldehyde-reactive agents such as ARP, we demonstrated the existence of aldehydes on the surface of macrophages. We synthesized biotinylated-penicillamine and it also binds to macrophages. Several proteins to which ARP binds were identified providing clues to the signal transduction pathways leading to macrophage activation. Biological consequences of this binding were investigated with a microarray study. ARP binding was also observed in the macrophage cell line, RAW264.7, and incubation with penicillamine stimulated the production of TNF-α, IL-6, and IL-23. Hydralazine and isoniazid, which are known to cause a lupus-like syndrome in humans and irreversibly bind to aldehyde groups, were also found to activate RAW264.7 cells. Th17 cells are prominent in autoimmune syndromes and Th17-associated cytokines such as IL-17 were elevated in the penicillamine-treated animals that developed autoimmunity. We have hypothesized that some drug-induced liver injury has an autoimmune component. A pilot study quantified serum concentrations of 26 cytokines/chemokines in patients with various forms of acute liver failure (ALF): idiosyncratic drug-induced ALF, acetaminophen-induced ALF, and viral hepatitis. IL-17 was elevated in 60% of patients with idiosyncratic drug-induced ALF, which supports an autoimmune component in these patients; however, it was also elevated in many cases of acetaminophen-induced ALF, presumably released by the innate immune system. These studies provide important insights into the mechanism of penicillamine-, hydralazine-, and isoniazid-induced autoimmunity and also provide clues to other IDRs that may have an autoimmune component.

Bendros nuomonės vertinant rizikos veiksnius, sąlygojančius kepenų pažeidimą gydant vaistais nuo tuberkuliozės ŽIV infekuotus ir neinfekuotus pacientus, sergančius tuberkulioze, nėra. ŽIV infekcijos įtaka šiam pažeidimui atsirastinėra išaiškinta. Daugelis darbų atlikta su nedideliu ŽIV infekuotų pacientų skaičiumi ir gauti rezultatai yra skirtingi. Darbo tikslas Nustatyti rizikos veiksnius, sąlygojančius sunkaus kepenų pažeidimo atsiradimą gydant vaistais nuo tuberkuliozės pirmus du tuberkuliozės gydymo mėnesius ŽIV infekuotus ir neinfekuotus ligonius, sergančius aktyvia tuberkulioze, taip pat nustatyti šio pažeidimo pasireiškimo dažnį bei pažeidimo atsiradimo laiką. Darbo uždaviniai 1. Išnagrinėti tuberkulioze sergančių bei gydomų nuo tuberkuliozės ligonių demografines, klinikines ypatybes bei kai kurių laboratorinių tyrimų duomenis tuberkuliozės gydymo pradžioje. 2. Nustatyti bei palyginti kepenų pažeidimo pasireiškimo dažnį bei atsiradimo laiką gydant vaistais nuo tuberkuliozės ŽIV infekuotus ir neinfekuotus pacientus. 3. Nustatyti ir palyginti demografinius, laboratorinius ir klinikinius rizikos veiksnius, galinčius turėti įtakos sunkiam kepenų pažeidimui atsirasti gydant vaistais nuo tuberkuliozės pirmus du tuberkuliozės gydymo mėnesius ŽIV infekuotus ir neinfekuotus ligonius. 4. Nustatyti vaistų, kurie pradėti vartoti kartu su per pirmą savaitę paskirtais vaistais nuo tuberkuliozės, įtaką kepenų pažeidimui atsirasti. / Although there are many hepatotoxicity risk factors describe for patients on antituberculosis therapy. However, the risk factors for liver injury and its occurence during this antituberculosis therapy have been assessed in HIV non-infected patients, they have rarely been assessed in HIV-infected patients, especially those treated for active tuberculosis. Most studies with HIV-infected patients on antituberculosis therapy have been carried out with a small amount of HIV-infected patients and results received are different. Aims and objectives The aim of this study is therefore to evaluate the incidence of severe liver injury in HIV-infected and non-infected patients on antituberculosis therapy, the time to its occurrence, and the clinical, biological and therapeutic risk factors for this injury. The objectives were as follows: 1. To investigate into demographic, clinical particularities and laboratory data of patients on antituberculosis treatment. 2. To define and compare the incidence of severe liver injury as well as the time of these occurrence in HIV-infected and non-infected patients on antituberculosis treatment. 3. To define and compare demographic, biological and clinical risk factors for severe liver injury in HIV-infected and non-infected patients on antituberculosis treatment within the first two month of this therapy. 4. To define the impact on liver injury occurrence of medications used in the first week of the tuberculosis treatment.

The aim of these studies was to identify circulating miRNAs that can be used as biomarkers in patients with paracetamol-induced liver injury. Whether the miRNAs discovered in humans could be back-translated to zebrafish with the aim of developing a liver toxicity model to replace rodent use was also investigated. First, the miRNA signature of DILI induced by paracetamol was defined. Plasma miRNAs were quantified in paracetamol overdose patients. A signature of 16 miRNAs was discovered that best separated patients with liver injury from those without liver injury. This signature was tested in a second cohort and resulted in the detection of paracetamol-induced liver injury with high specificity and sensitivity. At first presentation to hospital miR-122-5p was the most sensitive single miRNA and superior to ALT activity in predicting liver injury. In order to further qualify miR-122-5p, three detailed studies relevant to possible clinical scenarios were performed. The effect of acute alcohol ingestion (commonly co-ingested with paracetamol overdose) on circulating concentrations of miR-122-5p in healthy volunteers was investigated. Alcohol ingestion induced a small, non-clinically relevant, increase in miR-122-5p. The effect of chronic kidney disease (CKD) and haemodialysis (HD) on circulating miR-122-5p concentrations was explored because kidney dysfunction has been associated with a reduction in the concentration of circulating miRNAs. HD patients had lower concentrations of miR- 122-5p compared to healthy volunteers and CKD patients. To facilitate miRNA measurement outwith hospitals, miR-122-5p was measured in a blood drop from a finger prick. miR-122-5p was readily measurable in finger prick samples and concentrations were significantly higher in the blood drop from DILI patients compared with healthy volunteers. To complement miR-122-5p as a marker of toxicity, circulating paracetamol metabolites were measured in plasma samples from paracetamol overdose patients. A higher percentage of circulating metabolites formed by cytochrome P450 enzymes were present in patients with liver injury and these metabolites were superior to both ALT and paracetamol concentration with regard to early patient stratification. To reduce need for rodent studies, miRNAs were back-translated into zebrafish. In order to study circulating miR-122-5p in adult zebrafish, a bloodletting method by collecting blood retro-orbitally was developed. After studying different dosing regimens of paracetamol in adult and larvae zebrafish the model was determined to be too variable with regard to liver injury. A new drug, triptolide, originating from traditional Chinese medicine and responsible for DILI in China, was tested as an alternative model for drug-induced liver injury in zebrafish larvae. miRNA-122-5p decreased in zebrafish larvae after triptolide treatment and triptolide-induced liver injury could be tracked by fluorescent microscopy. Selective plane illumination microscopy was able to track the decrease in liver volume during triptolide exposure. In order to identify the toxic pathways involved in triptolide-induced liver injury, RNA-sequencing was performed. This identified KEGG pathways including ribosome, spliceosome and notch signalling as pathways affected by triptolide. In summary, miRNAs can be used as highly sensitive biomarkers to detect acute liver injury in patients and zebrafish. Zebrafish may represent an alternative model species to study DILI, further work is needed.

by Lawrence Chi-ming Chiu. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1994. / Includes bibliographical references (leaves 142-151). / Abstract --- p.i / Acknowledgments --- p.iv / Table of Contents --- p.v / List of Figures --- p.vii / List of Tables --- p.xi / List of Abbreviations --- p.xii / Chapter Chapter 1: --- Introduction / Chapter 1.1 --- Polysaccharide-peptide (PSP ) --- p.1 / Chapter 1.2 --- Paracetamol (APAP ) --- p.6 / Chapter 1.2.1 --- Metabolism of APAP --- p.9 / Chapter 1.2.2 --- Mechanisms of APAP toxicity --- p.11 / Chapter 1.2.3 --- Factors influencing the hepatotoxicity of APAP --- p.17 / Chapter 1.3 --- Aim of the present study --- p.23 / Chapter Chapter 2: --- Studies on the effects of PSP on APAP-hepatotoxicity and glutathione levels / Chapter 2.1 --- Introduction --- p.25 / Chapter 2.2 --- Materials and methods --- p.30 / Chapter 2.3 --- Results / Chapter 2.3.1 --- The effects of PSP on APAP-induced hepatotoxicity --- p.41 / Chapter 2.3.2 --- The acute and sub-chronic effects of PSP on glutathione in rats --- p.45 / Chapter 2.4 --- Discussions --- p.66 / Chapter Chapter 3: --- Studies on the effects of PSP on the covalent binding and metabolism of APAP / Chapter 3.1 --- Introduction --- p.79 / Chapter 3.2 --- Materials and methods --- p.85 / Chapter 3.3 --- Results / Chapter 3.3.1 --- The effects of PSP on the covalent binding of radiolabelled paracetamol (14C-APAP ) in vitro --- p.102 / Chapter 3.3.2 --- The effects of PSP on the metabolism of APAP --- p.107 / Chapter 3.4 --- Discussions --- p.119 / Chapter Chapter 4: --- Conclusion --- p.137 / References --- p.142

Wang Deqing. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (p. 236-277). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Avasarala Sreedevi. / "December 2004." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (p. 253-272) / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in partial fulfillment of the requirements for the degree of Master of Science in Medicine in Pharmacotherapy, Johannesburg, 2011 / Long term antiretroviral therapy (ART) use is known to cause various toxic adverse effects in patients. Hepato-toxicity is one of the most significant adverse effects which have been associated with all antiretroviral therapy drugs in South Africa and worldwide.

No description available.

acase@tulane.edu

Mitochondrial superoxide production during the early and late radiation response is increasingly recognized as a critical driver of oxidative damage and injury processes in mammalian cells. The role of Sirtuin 3, a key mitochondrial regulatory deacetylase, in preventing mitochondrial superoxide generation in conditions of nutrient and oxidative stress may be critical during the radiation response in mammalian liver. Because several tumor types express lower than normal levels of Sirtuin 3, the involvement of Sirtuin 3 in the radiation response may also provide clues to improving cancer radiation therapy and understanding the process of carcinogenesis. Studies of how the SIRT3 loss impacts the hepatic radiation response may also provide insight into the role of superoxide in normal liver physiology as well as in conditions of pathology. Increased superoxide production has largely been associated with disease, but oftentimes without clear demonstration of mechanism or even clear descriptions of pathogenesis. Here we identify a target of Sirtuin 3, the mitochondrial antioxidant enzyme manganese superoxide dismutase, and delineate the role that Sirtuin 3-mediated increases in manganese superoxide dismutase may be playing in the prevention of injury following biologically relevant doses of low linear energy transfer and high linear energy transfer radiation types including Cs-137 and Fe and Si particle radiation. Loss of Sirtuin 3 appears to correlate with decreases in hepatocellular carcinoma 16 months after 0.1 and 1 Gy doses of particle radiation known to increase hepatocellular carcinoma rates. These results indicate that Sirtuin 3 is a critical regulator of superoxide metabolism in the liver following whole body irradiation.